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Genomic analyses of primary liver cancer samples reveal a complex mutational landscape with vast intertumor and intratumor heterogeneity. Different primary liver tumors and subclones within each tumor display striking molecular and biological variations. Consequently, tumor molecular heterogeneity contributes to drug resistance and tumor relapse following therapy, which poses a substantial obstruction to improving outcomes of patients with liver cancer. There is an urgent need to the compositional and functional understanding of tumor heterogeneity. In this review, we summarize genomic and non-genomic diversities, which include stemness and microenvironmental causes of the functional heterogeneity of the primary liver cancer ecosystem. We discuss the importance and intricacy of intratumor heterogeneity in the context of cancer cell evolution. We also discuss methodologies applicable to determine intratumor heterogeneity and highlight the best-fit patient-derived in vivo and in vitro models to recapture the functional heterogeneity of primary liver cancer with the aim to improve future therapeutic strategies. Differences in liver cancer cells within individual tumors and between different tumors obstruct treatment and justify intensive research. Primary liver cancer is the second most lethal cancer worldwide and its incidence is increasing. Xin Wei Wang and colleagues at the National Cancer Institute in Bethesda, Maryland, USA, reviewed research on the genetic and non-genetic diversity of liver cancer cells. Extensive intra-tumor and inter-tumor heterogeneity contributes significantly to drug resistance and tumor relapse following therapy. The heterogeneity includes variations in stem cell character and other factors which can lead to different pathways of cancer progression. The authors discuss the methods available to analyze liver tumor heterogeneity and to use the results to devise optimum therapy strategies for individual patients. They conclude there is an urgent need to learn more about tumor cell heterogeneity in liver cancer.
Liu et al. (Mon,) studied this question.